WO1993008184A1 - Hiv protease inhibitors - Google Patents
Hiv protease inhibitors Download PDFInfo
- Publication number
- WO1993008184A1 WO1993008184A1 PCT/US1992/008758 US9208758W WO9308184A1 WO 1993008184 A1 WO1993008184 A1 WO 1993008184A1 US 9208758 W US9208758 W US 9208758W WO 9308184 A1 WO9308184 A1 WO 9308184A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- unsubstituted
- substituted
- compound
- phenyl
- Prior art date
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- 239000004030 hiv protease inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 208000015181 infectious disease Diseases 0.000 claims abstract description 22
- 208000030507 AIDS Diseases 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 108010010369 HIV Protease Proteins 0.000 claims abstract description 10
- 230000005764 inhibitory process Effects 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 230000002265 prevention Effects 0.000 claims abstract description 8
- -1 1,1-dioxo-tetrahydrothienyl Chemical group 0.000 claims description 20
- 229920006395 saturated elastomer Polymers 0.000 claims description 20
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
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- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 7
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
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- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 2
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- 230000002401 inhibitory effect Effects 0.000 claims 1
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- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- GLNWILHOFOBOFD-UHFFFAOYSA-N lithium sulfide Chemical compound [Li+].[Li+].[S-2] GLNWILHOFOBOFD-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 108700004029 pol Genes Proteins 0.000 description 1
- 101150088264 pol gene Proteins 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Definitions
- Merck Case 18583 This application is related to Merck case 18466.
- the present invention is concerned with compounds which inhibit the protease encoded by human immunodeficiency virus (HIV).
- HIV human immunodeficiency virus
- the compounds, or pharmaceutically acceptable salts thereof, are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS).
- the present invention also relates to
- a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
- This virus was previously known as LAV, HTLV-III, or ARV.
- a common feature of retfovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function.
- EPO 389898, EPO 346847, and EPO 432695 each disclose HIV protease inhibitors but the compounds are very different because they have an amino acid (or analog thereof) attached to the amino-terminal end of the transition state analog.
- EPO 432694 discloses synthetic intermediates which are different from the compounds of the present invention.
- the particular advantages of the compounds of the present invention are increased oral bioavailabilty and lower serum protein binding.
- HBT HOBT or HOBt 1-hydroxybenzotriazole hydrate
- This invention is concerned with the
- R 1 is a) 5- to 7- membered carbocylic ring which is either saturated, partially saturated or unsaturated, the carbocylic ring being unsubstituted or substituted with one or more of C 1-4 alkyl, C 2-4 alkenyl, C 1-3 alkoxy, halo-C 1-3 alkyl, aryl-C 1-3 alkyl, or C 3-5 cycloalkyl; or b) 5- to 7-membered heterocyle having one heteroatom selected from O or S, any of which heterocycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 2-4 alkenyl, oxo, C 3-5
- R 2 is a) C 1-5 alkyl, unsubstituted or substituted with one or more of -OH or C 1-3 alkoxy; or b) 5- to 7-membered carbocyclic ring which is either saturated, partially saturated or unsaturated, the carbocyclic ring being unsubstituted or substituted with one or more of C 1-4 alkyl, C 2-4 alkenyl, C 1-3 alkoxy, or hydroxy;
- R 3 is a) Phenyl unsubstituted or substituted with one or more of -OH or C 1-3 alkoxy; or b) C 5-7 cycloalkyl unsubstituted or substituted with one or more of -OH or C 1-3 alkoxy, or pharmaceutically acceptable salt or hydrate thereof.
- the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers or
- variable e.g., heterocycle, R 1 or R 2 , etc.
- alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); "alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
- Alkenyl is intended to include hydrocarbon claims of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl,
- Halo as used herein, means fluoro, chloro, bromo or iodo.
- aryl is intended to mean phenyl (Ph) or naphthyl.
- Carbocyclic is intended to mean any stable 5- to 7-membered carbon ring or 7- to 10-membered bicyclic carbon ring, any of which may be saturated or partially unsaturated.
- heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of O and S, and wherein the sulfur heteroatoms may optionally be oxidized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include benzopyranyl, benzothiopyranyl,
- the pharmaceutically-acceptable salts of the compounds of Formula I include the
- non-toxic salts or the quaternary ammonium salts of these compounds which are formed, e.g., from inorganic or organic acids.
- acid addition salts include acetate, adipate, alginate, aspartate, benzoate, bisulfate, citrate, digluconate, dodecylsulfate, fumarate, glycerophosphate,
- R 1 is a 5- to 7-membered heterocycle having one
- heteroatom selected from O or S, any of which heterocycle is unsubstituted or substituted with one or more of C 1-4 alkyl, C 2-4 alkenyl, oxo or C 1-3 alkoxy;
- R 2 is C 1-5 alkyl, unsubstituted or substituted with one or more of -OH;
- R 3 is phenyl unsubstituted or substituted with -OH or C 1-3 alkoxy.
- a third embodiment is further limited to compounds wherein:
- R 1 is 1,1-dioxo-tetrahydrothienyl or
- R 2 is t-butyl or 2-methylpropyl
- R 3 is phenyl
- R 1 is tetrahydrofuran-3-yl or 1,1-dioxo-tetrahydrothien-3-yl, unsubstituted or substituted with methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, or propenyl.
- R 1 is a 5- to 7-membered heterocycle having one S heteratom, said heterocycle unsubstituted or substituted with one or more of C 1-4 alkyl, oxo or C 3-5 cycloalkyl;
- R 2 is C 1-5 alkyl
- R 3 is phenyl
- R 1 is 1,1-dioxotetrahydrothien-3-yl, unsubstituted or substituted with C 1-4 alkyl, or C 3-5 cycloalkyl;
- R 2 is C 1-5 alkyl
- R 3 is phenyl.
- Most preferred compounds of this invention include the following:
- the decahydro-isoquinol-ine intermediate 5 is synthesized by a first reaction of L-phenylalanine with formaldehyde and concentrated HCl to produce 2, as also described in Skiles, J.W. et al., J. Med. Chem. 29, 784 (1986) Hein, G.E., et al., J. Am. Chem. Soc. 48, 4487 (1962) and Hayasnik, K. et al., Chem. Pharm. Bull. 31, 312 (1983). Subsequent hydrogenation with catalysts such as Pt or Rh yields 3, which is then derivatized with an NH-protecting group such as Boc to give 4.
- catalysts such as Pt or Rh
- Catalytic asymmetric or Sharpless epoxidation to produce 8 is performed by the methods of Gao, Y. et al., J. Am. Chem. Soc. 109, 5765 (1987).
- Regioselective azide opening of the 2,3-epoxy alcohol 8 to give 9 is facilitated by titanium according to Caron, M. et al., J. Org. Chem. 53, 5185 (1988).
- Example 2 illustrates but does not limit Scheme II.
- Condensation of the azide epoxide 10 with the decahydro-isoquinoline intermediate 5 is performed by, for example, heating a mixture in refluxing
- the compounds of the present invention include but are not limited by the following Table:
- the compounds of the present invention are useful in the inhibition of HIV protease, the
- HIV human immunodeficiency virus
- Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection:
- the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, accidental needle stick, or exposure to patient blood during surgery.
- the compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds.
- the compounds of this invention are useful for. isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
- the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV protease, e.g., by competitive inhibition.
- the compounds of this invention are commercial products to be sold for these purposes.
- the compounds of the present invention may be administered orally,
- parenterally including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers,
- the treatment involves
- a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention, or a
- compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
- compositions When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art.
- microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art.
- microcrystalline cellulose may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders,
- compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable
- injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or
- solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
- compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating agent.
- excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
- patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age of the patient, body weight, general health, sex, diet, mode and time of
- the present invention is also directed to combinations of the HIV protease-inhibitory compounds with one or more agents useful in the treatment of AIDS,
- Step 1 Preparation of cis-N-tert-butoxycarbonyl- 3-carboxydecahydro-isoquinoline
- Example 4 was reacted with 27 ⁇ l Et 3 N, 5 mL CH 2 Cl 2 and 50 mg of the product of Example 5 was stirred at 25oC for 12 hrs., then concentrated to dryness, triturated (hexanes), giving the title compound, mp 80-82°C. Calc for C 29 H 45 N 3 O 5 ⁇ 0.25H 2 O (520.202)
- Step A Preparation of hexahydrofuro[2,3b]furan-3a- yl succinimidyl carbonate:
- Step B Preparation of N-(2(R)-hydroxy-1(S)- indanyl)-5(S)-(hexahydrofuro[2,3b]- furanyl-3a-oxycarbonylamino)-4(S)- hydroxy-6-phenyl-2(R)-(4-(2-(4-morpholinyl)ethoxy)phenyl)methyl hexanamide:
- Buccinimidyl carbonate and 0.060 mL of triethyl amine were stirring for 12 hours, the mixture was diluted with 50 mL of chloroform, washed with 10 mL of sat'd. sodium bicarbonate, and concentrated to dryness.
- the boronate thus obtained was oxidized with 100 ml of 3 N sodium hydroxide and 12.5 ml of 30% hydrogen peroxide.
- the reaction mixture was stirred at room temperature for 6h and then diluted with 200 ml of ether.
- the layers were separated and the aqueous layer was extracted with ether (2 ⁇ 100 ml).
- the combined organic extracts were dried over anhydrous Na 2 SO 4 and evaporated.
- the residue was loaded over a silica gel column and eluted first with hexanes to remove a-pinene and then with 25% EtOAc in hexanes to provide
- Ethyl 3-mercaptopropionate (22.46 g) was dissolved in absolute ethanol (60 mL) and the solution was cooled to -20°C. To it was added sodium ethoxide solution in ethanol (62.5 mL of 21%). A solution of ethyl 2-bromoisovalerate (35 g) in absolute ethanol (60 mL) was added slowly. The reaction mixture was stirred for 2 hours while the reaction temperature was allowed to warm to room temperature. Saturated NH 4 Cl (150 mL) was added to the reaction mixture and organic layer was separated. The aqueous layer was extracted with ethyl acetate (100 mL ⁇ 3). The combined organic layers were dried over Na 2 SO 4 and concentrated. Sodium (0.88 g) was dissolved in absolute ethanol (40 mL) at 0°C. and the solution was concentrated. The residue was
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- Tropical Medicine & Parasitology (AREA)
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- Molecular Biology (AREA)
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Abstract
Oligopeptide analogs are described. These compounds are useful in the inhibition of HIV protease, the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
Description
TITLE OF THE INVENTION
HIV PROTEASE INHIBITORS
This application is a continuation-in-part of U.S. Serial No. 07/781,470, filed October 23, 1991,
Merck Case 18583. This application is related to Merck case 18466.
The present invention is concerned with compounds which inhibit the protease encoded by human immunodeficiency virus (HIV). The compounds, or pharmaceutically acceptable salts thereof, are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS).
The present invention also relates to
pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS & viral
infection by HIV.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retfovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function.
Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N.E., et. al., Proc. Natl. Acad. Sci. USA, 85, 4686 (1988), demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of
immature, non-infectious virus particles. These results suggest that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame
[Ratner, L. et al . , Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature 329. 351 (1987)].
Applicants demonstrate that the compounds of this invention are inhibitors of HIV protease.
Related art includes Hoffman-LaRoche EPO applications. EPO 389898, EPO 346847, and EPO 432695
each disclose HIV protease inhibitors but the compounds are very different because they have an amino acid (or analog thereof) attached to the amino-terminal end of the transition state analog. EPO 432694 discloses synthetic intermediates which are different from the compounds of the present invention.
The particular advantages of the compounds of the present invention are increased oral bioavailabilty and lower serum protein binding.
BRIEF DESCRIPTION OF THE INVENTION
Compounds of formula I, as herein defined, are disclosed. These compounds are useful in the inhibition of HIV protease, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS, either as compounds,
pharmaceutically acceptable salts, hydrates or esters, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods ""of treating infection by HIV are also disclosed.
ABBREVIATIONS
Activating Agent
HBT (HOBT or HOBt) 1-hydroxybenzotriazole hydrate
Condensing Agent
EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED
EMBODIMENTS
This invention is concerned with the
compounds of Formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV protease, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows :
R1 is a) 5- to 7- membered carbocylic ring which is either saturated, partially saturated or unsaturated, the carbocylic ring being unsubstituted or substituted with one or more of C1-4 alkyl, C2-4 alkenyl, C1-3 alkoxy, halo-C1-3 alkyl, aryl-C1-3 alkyl, or C3-5 cycloalkyl; or
b) 5- to 7-membered heterocyle having one heteroatom selected from O or S, any of which heterocycle is unsubstituted or substituted with one or more of C1-4 alkyl, C2-4 alkenyl, oxo, C3-5
cycloalkyl, or C1-3 alkoxy;
R2 is a) C1-5 alkyl, unsubstituted or substituted with one or more of -OH or C1-3 alkoxy; or b) 5- to 7-membered carbocyclic ring which is either saturated, partially saturated or unsaturated, the carbocyclic ring being unsubstituted or substituted with one or more of C1-4 alkyl, C2-4 alkenyl, C1-3 alkoxy, or hydroxy;
R3 is a) Phenyl unsubstituted or substituted with one or more of -OH or C1-3 alkoxy; or b) C5-7 cycloalkyl unsubstituted or substituted with one or more of -OH or C1-3 alkoxy, or pharmaceutically acceptable salt or hydrate thereof.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers or
enantiomers, with all isomeric forms being included in the present invention.
When any variable (e.g., heterocycle, R1 or R2, etc.) occurs more than one time in any constituent
or in formula I, its definition on each occurrence is independent of its definition at every other
occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein except where noted, "alkyl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Alkenyl" is intended to include hydrocarbon claims of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl,
propenyl, butenyl, pentenyl, and the like. "Halo", as used herein, means fluoro, chloro, bromo or iodo.
As used herein, with exceptions as noted, "aryl" is intended to mean phenyl (Ph) or naphthyl.
"Carbocyclic" is intended to mean any stable 5- to 7-membered carbon ring or 7- to 10-membered bicyclic carbon ring, any of which may be saturated or partially unsaturated.
The term heterocycle or heterocyclic, as used herein except where. noted, represents a stable 5- to 7-membered monocyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of O and S, and wherein the sulfur heteroatoms may optionally be oxidized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The
heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include benzopyranyl, benzothiopyranyl,
tetrahydrofuryl, tetrahydropyranyl, and
tetrahydrothienyl.
The pharmaceutically-acceptable salts of the compounds of Formula I (in the form of water- or oil- soluble or dispersible products) include the
conventional non-toxic salts or the quaternary ammonium salts of these compounds, which are formed, e.g., from inorganic or organic acids. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, bisulfate, citrate, digluconate, dodecylsulfate, fumarate, glycerophosphate,
hemisulfate, hydrochloride, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, succinate and tartrate. In a preferred embodiment of this invention,
R1 is a 5- to 7-membered heterocycle having one
heteroatom selected from O or S, any of which heterocycle is unsubstituted or substituted with one or more of C1-4 alkyl, C2-4 alkenyl, oxo or C1-3 alkoxy;
R2 is C1-5 alkyl, unsubstituted or substituted with one or more of -OH;
R3 is phenyl unsubstituted or substituted with -OH or C1-3 alkoxy.
A third embodiment is further limited to compounds wherein:
R1 is 1,1-dioxo-tetrahydrothienyl or
tetrahydrofuranyl, unsubstituted or
substituted with C1-4 alkyl, C2-4 alkenyl or C1-3 alkoxy;
R2 is t-butyl or 2-methylpropyl;
R3 is phenyl.
A fourth embodiment is further limited to compound wherein:
R1 is tetrahydrofuran-3-yl or 1,1-dioxo-tetrahydrothien-3-yl, unsubstituted or substituted with methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, or propenyl.
In a fifth preferred embodiment,
R1 is a 5- to 7-membered heterocycle having one S heteratom, said heterocycle unsubstituted or substituted with one or more of C1-4 alkyl, oxo or C3-5 cycloalkyl;
R2 is C1-5 alkyl;
R3 is phenyl.
A sixth embodiment is further limited to:
R1 is 1,1-dioxotetrahydrothien-3-yl, unsubstituted or substituted with C1-4 alkyl, or C3-5 cycloalkyl;
R2 is C1-5 alkyl;
R3 is phenyl.
Most preferred compounds of this invention include the following:
A:
cis-N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-[3(S)-tetrahydrofuranyloxycarbonylamino]-butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide hydrate; or
B:
Cis-N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-[3(S)-1,1-dioxotetrahydrothien-3-yloxy-carbonylamino]-butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide hydrate;
C:
N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)- [1,1-dioxo-2(R)-methylethyl-3(R)-tetrahydrothienyloxycarbonylamino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide, or pharmaceutically acceptable salt thereof.
The compounds of the present invention are prepared in accordance with Schemes I-IV.
SCHEME I
The decahydro-isoquinol-ine intermediate 5 is synthesized by a first reaction of L-phenylalanine with formaldehyde and concentrated HCl to produce 2, as also described in Skiles, J.W. et al., J. Med. Chem. 29, 784 (1986) Hein, G.E., et al., J. Am. Chem. Soc. 48, 4487 (1962) and Hayasnik, K. et al., Chem. Pharm. Bull. 31, 312 (1983). Subsequent hydrogenation with catalysts such as Pt or Rh yields 3, which is then derivatized with an NH-protecting group such as Boc to give 4.
Coupling with tBuNH2 followed by deprotection affords 5. Example 1 illustrates but does not limit Scheme I.
SCHEME II
Catalytic asymmetric or Sharpless epoxidation to produce 8 is performed by the methods of Gao, Y. et al., J. Am. Chem. Soc. 109, 5765 (1987). Regioselective azide opening of the 2,3-epoxy alcohol 8 to give 9 is facilitated by titanium according to Caron, M. et al., J. Org. Chem. 53, 5185 (1988). Example 2 illustrates but does not limit Scheme II.
SCHEME III
Condensation of the azide epoxide 10 with the decahydro-isoquinoline intermediate 5 is performed by, for example, heating a mixture in refluxing
isopropanol, to give the azido-alcohol 11 in good yield. Reduction over palladium on carbon yields the amine 12, which is then reacted with the appropriate N-substituted succinimide 13 in the presence of e.g. TEA to give compounds of Formula I or 14 Examples 3-6 illustrate but do not limit Scheme III.
SCHEME IV
SCHEME IV cont ' d
Alternatively, for the synthesis of cyclic sulfone compounds such as compound 21, the di-(2-pyridyl) carbonate method of urethane coupling
according to A.K. Ghosh, T.T. Duong and S.P. McKee, Tetrahedron Letters, 32, 4251 (1991) may be employed (Scheme IV). The (S)-butane-1,2,4-triol-2-tetrahydropyranyl ether 15 is prepared according to K. Mori, T. Takigawa and T. Matsuo, Tetrahedron, 35, 933 (1979) and converted into the 3(S)-hydroxytetrahydrothiophene
18 as shown in Scheme IV. Selective oxidation of the coupled tetrahydrothiophene 20 into the sulfolane 21
was effected by catalytic osmium tetraoxide in the presence of N-methylmorpholine N-oxide. Examples 7-12 illustrate but do not limit Scheme IV.
Other substituents for R2 and R3 in Formula I are readily prepared by those skilled in the art, by substituting and/or protecting appropriate groups in the schemes outlined above.
The compounds of the present invention include but are not limited by the following Table:
The compounds of the present invention are useful in the inhibition of HIV protease, the
prevention or treatment of infection by the human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS.
Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection:
AIDS, ARC (AIDS related complex), both symptomatic and asymtomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for. isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV protease, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
For these purposes, the compounds of the present invention may be administered orally,
parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally,
in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers,
adjuvants and vehicles.
Thus, in accordance with the present invention there is further provided a method of
treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves
administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention, or a
pharmaceutically-acceptable salt thereof.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art. As
immediate release tablets, these compositions
may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders,
disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or
inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance
bioavailability, flourocarbons, and/or other
solubilizing or dispersing agents known in the art.
The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or
solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating
excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
Dosage levels of the order of 0.02 to 5.0 or
10.0 grams-per-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to-five times higher. For example, infection by HIV is effectively treated by the administration of from 10 to 50 milligrams of the compound per kilogram of body weight from one to three times per day. It will be understood, however, that the specific dose
level and frequency, of dosage for any particular
patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age of the patient, body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV protease-inhibitory compounds with one or more agents useful in the treatment of AIDS,
EXAMPLE 1
Preparation of cis-N-tert-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide. Compound 5
Step 1: Preparation of cis-N-tert-butoxycarbonyl- 3-carboxydecahydro-isoquinoline
A suspension of L-3-carboxy-1,2,3,4-tetrahydroisoquinoline, 21.3 g, prepared as described by G.E. Hein, et al., J. Am. Chem. Soc, 84, 4487 (1962), in 650 mL of ethanol and 650 mL of water was shaken with 21.3 g of 5% rhodium on carbon under 15 atm of hydrogen at 50°C until 3 molar equivalents of hydrogen were consumed (6h). After cooling the catalyst was filtered off and the solvents removed under reduced pressure. After drying, the residue was recrystallized from ethanol affording 8 g of L-cis-3-carboxy
decahydroisoquinoline. To a solution of 5 g of
L-cis-3-carboxydecahydrosoquinoline in 75 mL of dioxane and 185 mL of dilute sodium carbonate (pH8) was added 7 g of di-tert-butyldicarbonate. After 2 days stirring at room temperature, the mixture was acidified with IN HCl until pH is 3 and extracted with three 100 mL portions of ethyl acetate. After concentration and drying there was obtained 4.1 g of a white solid. Step 2: Preparation of cis-N-tert-butyl-decahydro- (4aS.8aS)-isoquinoline-3(S)-carboxamide
To a stirred solution of cis-N-tert-butoxycarbonyl-3-carboxydecahydro-isoquinoline (the product of Step 1), 4.1 g, in 100 mL of tetrahydrofuran cooled to -20°C was added 2.8 mL of N-methylmorpholine
and 2.42 mL of isobutylchloroformate. After 15 min, 2.4 mL of tert-butylamine was added and the mixture allowed to warm to room temperature and stir
overnight. The mixture was diluted with 200 mL of ethyl acetate and 100 mL of 10% citric acid. The organic layer was washed with saturated sodium
bicarbonate, dried ( MgSO4) and concentrated. The resulting white solid was dissolved in 50 mL of ice cold methylene chloride and 25 mL of trifluoroacetic acid. After warming and stirring for 2 h, the solvents were removed under reduced pressure. The residue was dissolved in 100 mL of methylene chloride, washed with 50 mL of saturated sodium bicarbonate, dried and
concentrated. The product, 3.0 g, solidified on
standing.
EXAMPLE 2
Preparation of 3(S)-azido-(1,2R)-epoxy-4-phenyl- butane. Compound 10
A quantity of CuCN, 2.43 g, was added to a solution of butadiene monooxide, 19 g, in 500 mL anhydrous tetrahydrofuran and the mixture was cooled to -78°C. Phenyl magnesium bromide solution in ether, 32 mmol, was added dropwise to this mixture. The reaction mixture was warmed to 0°C and was stirred until the reaction became homogeneous. The reaction mixture was cooled to -78°C and 0.29 mole of phenylmagnesium bromide solution in ether was added dropwise for 30 min. The reaction mixture was allowed to warm to room temperature with stirring then quenched by slow
addition of saturated NH4Cl (50 mL) followed by NH4OH (30 mL), saturated NH4Cl (200 mL) and H2O (100 mL). Aqueous layer was extracted with two 200 mL portions of ethyl acetate. Combined organic layers were dried and concentrated. The residue was distilled under vacuum (0.1 torr) at 100°C to give trans-4-phenyl-2- butene-1-ol (38.9 g, 79% pure).
A mixture of powdered 4Å molecular sieves, 3 g, titanium tetraisopropoxide, 1.5 mL, and diethyl D-tartrate, 1.1 mL, in anhydrous methylene chloride (350 mL) was cooled to -20°C and tert-butylhydroperoxide solution in isooctane, 210 mmol, was added slowly with stirring. After 30 minutes at -20°C a solution of trans-4-phenyl-2-butene-1-ol, 15.3 g, in anhydrous methylene chloride (50 mL) was addsd dropwise
for 20 min at -20°C. The reaction mixture was aged at -20°C in a freezer for 20 hours. Water (40 mL) was added to the reaction mixture and after 30 minutes at 0°C, 30% NaOH in brine (6 mL) was added. The resulting mixture was stirred for 1 h at room temperature. The organic phase was separated and the aqueous layer was extracted with two 30 mL portions of methylene
chloride. Combined organic layers were dried over Na2SO4, diluted with toluene (300 mL) and
concentrated. Chromatography on silica gel with 40% ethyl acetate in hexane gave (2R, 3R)-epoxy-4- phenylbutan-1-ol (10.3 g).
A solution of titanium tetraisopropoxide, 5.6 mL, and azidotrimethylsilane, 5.0 mL, in anhydrous benzene (100 mL) was refluxed for 5 h. To this
refluxing mixture was added a solution of (2R,
3R)-epoxy-4-phenylbutan-1-ol, 2.6 g, in anhydrous benzene (10 mL). The reaction mixture was refluxed for 15 min, cooled to room temperature and quenched by addition of 5% H2SO4 (150 mL). After stirring the resulting biphasic mixture for 1 h, the organic layer was separated and the aqueous layer was extracted with two 20 mL portions of ethyl acetate. Combined organic layers were washed with saturated sodium bicarbonate (50 mL), dried over MgSO4 and concentrated. The oily azidodiol product was dissolved in chloroform (30 mL) and 2-acetoxyisobutyryl chloride, 2.5 mL, was added. After stirring for 5 h at room temperature, saturated sodium bicarbonate (50 mL) was added and the resulting biphasic mixture was stirred for 10 min. The aqueous
layer was extracted with two 30 mL portions of
chloroform. Combined organic layers were dried over Na2SO4 and concentrated. The residue was dissolved in anhydrous tetrahydrofuran (10 mL) and solid NaOMe, 0.614 g, was added. After stirring for 3 h at room temperature, saturated NH4Cl (20 mL) was added and the mixture extracted with two 20 mL portions of ethyl acetate. Combined organic layers were dried over MgSO4 and concentrated. Chromatography on silica gel with 8% ethyl acetate in hexanes gave 3(S)-azido-(1, 2R)-epoxy-4-phenylbutane (1.32 g) as an oil.
EXAMPLE 3 Preparation of cis-N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-azidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide. Compound 11
A mixture of 6.46 g of cis-N-tert-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide
(product of Example 1) and 10.3 g of 3(S)-azido-(1,2R)-epoxy-4-phenylbutane (product of Example 2) in 200 mL of isopropanol was heated to 80°C overnight then concentrated to dryness under reduced pressure.
Recrystallization from ethyl acetate-hexanes gave 9.63 g of product of melting point 149-50°C.
EXAMPLE 4
Preparation of cis-N-tert-butyl-decahydro-2[2(R)- hydroxy-4-phenyl-3(S)-aminobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide. Compound 12
A solution of 5.0 g of cis-N-tert-butyl- decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-azidobutyl]- (4aS,8aS)-isoquinoline-3(S)-carboxamide (product of Example 3) in 200 mL of tetrahydrofuran and 50 mL of methanol was shaken with 1 g of 10% palladium on carbon catalyst under an atmosphere of hydrogen for 48 h.
Removal of the catalyst by filtration and concentration under reduced pressure gave 4.68 g of product as a white solid of melting point 165-166°C.
EXAMPLE 5
Preparation of 3(S)-tetrahydrofuranyl succinimidyl carbonate. Compound 13
A solution of 20 mL of 12.5% phosgene in toluene and 1.0 g of (S)-(+)-3-hydroxytetrahydrofuran was aged in a stoppered flask for 48 hours. The solvents were removed under reduced pressure and the residue dissolved in 30 mL of anhydrous acetonitrile, then cooled in an ice bath. To this cold solution was added 1.7 g of N-hydroxysuccinimide and 1.9 mL of triethylamine. The mixture was aged for 12 hours at 25ºC, then concentrated to dryness. The residue was dissolved in 200 mL of ethyl acetate, washed with 2 × 50 mL of water, dried over MgSO4 and concentrated to
dryness under reduced pressure. The oily residue was dissolved in 10 mL of ethyl acetate passed through a 300 mL of silica gel, eluting with ethyl acetate.
Concentration of the eluate to dryness gave 2 g of product as a white crystalline solid.
EXAMPLE 6
Preparation of cis-N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-[3(S)-tetrahydrofuranyloxycarbonylamino]-butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide. Compound A.
A quantity of 100 mg of the product of
Example 4 was reacted with 27 μl Et3N, 5 mL CH2Cl2 and 50 mg of the product of Example 5 was stirred at 25ºC for 12 hrs., then concentrated to dryness, triturated (hexanes), giving the title compound, mp 80-82°C. Calc for C29H45N3O5●0.25H2O (520.202)
%C=66.95, %H=8.81, %N=8.08
Found: %C=67.11, %H=8.92, %N=7.85
EXAMPLE 7 Preparation of 2(S)-butane-1,2,4-triol-1,4-dimesylate 2-THP-ether. Compound 16
(S)-Butane-1,2,4-triol-2-THP ether (Compound 15), 15.0 g, was dissolved in 75 mL of dry methylene chloride and 37 mL of triethylamine and cooled to
-10°C. Methanesulfonyl chloride, 10.2 ml, was added dropwise over 10 minutes. After stirring at 24°C for 12 hours, the solvent was evaporated and the residue was taken up in ethyl acetate and washed with saturated aqueous NaHCO3 (1×150 ml), water (1×150 mL) and brine and dried over anhydrous Na2SO4. Filtration and concentration under reduced pressure afforded 12 g of the title compound as a brown oil. EXAMPLE 8
Preparation of 3(S)-hydroxytetrahydrothiophene
THP-ether. Compound 17 A solution of 2(S)-butane-1,2,4-triol-1,4-dimesylate 2-THP-ether, 12 g, and lithium sulfide, 8 g, in 250 mL of dry DMF was heated to 70ºC for 12 hours. After cooling to 0°C, ether (400 ml) and water (400 ml) were added and the layers were separated. The aqueous layer was reextracted with ether (1×100 ml) and the combined organic layers were washed with water (1×150 mL) and brine and dried over anhydrous Na2SO4.
Filtration and evaporation of the solvent gave a residue which was taken up in CH2Cl2 (150 ml) and dried with Na2SO4. Filtration and concentration under reduced pressure afforded 4.2 g of the title compound as a yellow oil.
EXAMPLE 9
Preparation of 3(S)-hydroxytetrahydrothiophene,
Compound 18
A solution of 3(S)-hydroxytetrahydrothiophene THP-ether, 4.2 g, and p-toluenesulfonic acid monohydrate, 0.10 g, in 25 mL of methanol was stirred for 12 hours. Saturated aqueous NaHCO3 (10 ml) was added and stirring was continued for 30 min.
Evaporation of the solvents gave a residue which was extacted with ethyl acetate (100 ml) and water (10 ml). The layers were separated and the aqueous layer was reextracted with ethyl acetate (3×20 ml) and the combined organic layers were dried over anhydrous
Na2SO4. Filtration and concentration under reduced pressure gave a residue which was purified by
chromatography over silica gel. Elution with 1:1 ethyl acetate/hexanes afforded 2.5 g of the title compound as a clear colorless oil.
EXAMPLE 10
Preparation of 3(S)-tetrahydrothienyl-2-pyridyl
carbonate. Compound 19
To a stirred solution of 3(S)-hydroxytetrahydrothiophene, 0.150 g, and di(2-pyridyl) carbonate, 0.470 g in 10 mL of dry methylene chloride was added 0.301 ml of triethylamine. After stirring for 12 hours, the mixture was diluted with methylene chloride and washed with saturated aqueous NaHCO3 (10 ml) and
brine and dried over anhydrous Na2SO4. Filtration and concentration under reduced pressure gave a residue which was purified by chromatography over silica gel. Elution with 1:3 ethyl acetate/hexanes afforded 0.30 g of the title compound as an oil.
EXAMPLE 11
Preparation of cis-N-tert-butyl-decahydro-2[2(R)- hydroxy-4-ρhenyl-3(S)-[3(S)-tetrahydrothien-3-yloxycarbonylamino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxa mide. Compound 20
A solution of 3(S)-tetrahydrothienyl 2-pyridyl carbonate, 0.30 g, and cis-N-tert-butyl- decahydro-2[2(R)-hydroxy-4-ρhenyl-3(S)-aminobutyl]-(4aS, 8aS)-isoquinoline-3(S)-carboxamide (Compound 12), 0.40 g in 30 mL of dry methylene chloride was stirred for 12 hours. The mixture was diluted with methylene chloride and washed with saturated aqueous NaHCO3 (10 ml), brine and dried over anhydrous Na2SO4. Filtration and
concentration under reduced pressure gave a residue which was purified by chromatography over silica gel. Elution with 1:1 ethyl acetate/hexanes afforded 0.350 g of the title compound as a white solid: mp 106-8°C.
Elemental analysis, calc'd. for
C29H45N3O4S × 0.35 H2O (538.06):
C, 64.73; H, 8.56; N, 7.81
Found: C, 64.70; H, 8.31; N, 7.83.
EXAMPLE 12
Preparation of cis-N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-[3(S)-1,1-dioxotetrahydrothien-3-yloxycarbonylamino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide. Compound 21
To a stirred solution of 0.350 g of cis-N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)- [3(S)-tetrahydrothien-3-yloxycarbonylamino]butyl]- (4aS,8aS)-isoquinoline-3(S)-carboxamide in 30 mL of acetone and 10 ml of water cooled to 0°C was added 0.350 mL of a 2.5% solution of osmium tetroxide in 2-methyl-2-propanol. The mixture was stirred to 24°C for 12 hours and concentrated under reduced pressure. The residue was taken up in ethyl acetate (50 ml) and water (20 ml). The layers were separated and the organic layer was washed with brine and dried over anhydrous Na2SO4. Filtration and concentration under reduced pressure gave a residue which was purified by chromatography over silica gel. Elution with 5:95 methanol/chloroform afforded 0.325 g of the title compound as a white solid: mp 111-113°C. Elemental analysis, calc'd. for C29H45N3O6S × 0.25 CHCl3 (593.61)
C, 59.18; H, 7.68; N, 7.08
Found: C, 59.25; H, 7.52; N, 7.21
EXAMPLE 13 Preparation of hexahydrofuro[2,3b]furan-3a-ol To a stirred solution of 10 g of 2-n-butyloxy-3-allyl-tetrahydrofuran-3-ol (prepared as described by M. Jalali-Naini and J.Y. Lallemand, Tetrahedron Letters, pp 497-500, 1986) in 10 mL of methanol and 220 mL of methylene chloride cooled to -78°C was added a stream of ozone until a blue color persisted. The mixture was purged with nitrogen, warmed to 0°C and diluted with 100 mL of ethanol. To this mixture was added 5 g of NaBH4. After aging at 25°C for 6 hours, the solvents were removed under reduced pressure and the residue partitioned between 50 mL of 10% citric acid and 3 × 100 mL of methylene chloride. The organic extracts were dried over MgSO4 and concentrated to ca. 200 mL. To this stirred solution was added 0.10 g of p-toluenesulfonic acid monohydrate. The mixture was heated at reflux for 24 hours, then concentrated to dryness under reduced pressure. Evaporative
distillation of the residue at 0.1 mm (110-130°C) gave 2 g of the title compound. EXAMPLE 14
Preparation of tertiary alcohol urethanes
Step A: Preparation of hexahydrofuro[2,3b]furan-3a- yl succinimidyl carbonate:
To a stirred solution of 1 g of hexahydrofuro[2,3b]furan-3a-ol in 25 mL of 12.5% phosgene in toluene cooled to -10°C was added 1 mL of pyridine.
The mixture was allowed to warm to 25°C and stir for 4 hours, then concentrated to dryness under reduced pressure. The oily residue after drying under vacuum (1.3 g) was dissolved in 30 mL of anhydrous
acetonitrile, then cooled in an ice bath. To this cold solution was added 1.14 g of N-hydroxysuccinimide and 1.3 mL of triethylamine. The mixture was aged for 48 hours at 25°C, then concentrated to dryness. The residue was dissolved in 200 mL of ethyl acetate, washed with 2 × 50 mL of water, dried over MgSO4 and concentrated to dryness under reduced pressure.
Chromatography of the residue with 20% ethyl acetate in methylene chloride gave 0.49 g of product as a white crystalline solid.
Step B: Preparation of N-(2(R)-hydroxy-1(S)- indanyl)-5(S)-(hexahydrofuro[2,3b]- furanyl-3a-oxycarbonylamino)-4(S)- hydroxy-6-phenyl-2(R)-(4-(2-(4-morpholinyl)ethoxy)phenyl)methyl hexanamide:
To a stirred suspension of 100 mg of the product of Example 4 in 15 mL of methylene chloride was added 90 mg of hexahydrofuro[2,3b]furan-3a-yl
Buccinimidyl carbonate and 0.060 mL of triethyl amine. After stirring for 12 hours, the mixture was diluted with 50 mL of chloroform, washed with 10 mL of sat'd. sodium bicarbonate, and concentrated to dryness.
Chromatography using 8% MeOH in CHCl3 gave 80 mg of product as a white crystalline solid.
Calc'd for C41H51N3O9 C, 67.47 H, 7.07 N, 5.76
Found: C, 67.45 H, 6.90 N, 5.77.
EXAMPLE 15
Preparation of 6(R)-methoxy-3(S)-hydroxy-tetrahydro-2H-pyran and 6(S)-methoxy-3(S)-hydroxy- tetrahydro-2H-pryan
To a stirred suspension of (-)-diisopinocamphenylborane (100 mmol in 40 ml of THF) at 0°C was added 9.1 ml of 6(SR)-methoxy-2,3-dihydro-2H-pyran. The reaction mixture was stirred at 0°C for 12h. After this period, the reaction temperature was raised to 25°C and 22.4 ml of freshly distilled acetaldehyde was added dropwise for 30 min. The resulting mixture was stirred at 25°C for 6h and then excess of acetaldehyde was removed under reduced pressure and to it 80 ml of THF was added. The boronate thus obtained was oxidized with 100 ml of 3 N sodium hydroxide and 12.5 ml of 30% hydrogen peroxide. The reaction mixture was stirred at room temperature for 6h and then diluted with 200 ml of ether. The layers were separated and the aqueous layer was extracted with ether (2×100 ml). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated. The residue was loaded over a silica gel column and eluted first with hexanes to remove a-pinene and then with 25% EtOAc in hexanes to provide
6(R)-methoxy-3(S)-hydroxy-tetrahydro-2H-pyran (major) and 6(S)-methoxy-3(S)-hydroxy-tetrahydro- 2H-pyran (minor) as colorless oil.
EXAMPLE 16
Preparation of 1-Benzyloxy-2(S)-hydroxy-4-pentene
Copper (I)cyanide (120 mg, 1.34 mmol) was added to a solution of (R)-(-)-2-(benzyloxymethyl)-oxirane (2.4 g, 14.6 mmol) in dry THF (200 ml). This mixture was cooled to.-78ºC under argon atmosphere. A solution of vinylmagnesium bromide in THF (26 ml, 1M, 26 mmol) was added slowly to the epoxide solution at -78°C. The reaction mixture was stirred for 5 hours while the reaction temperature was allowed to warm to 0°C. Saturated aqueous NH4Cl and NH4OH were added to the reaction mixture till the reaction mixture became clear. Organic layer was separated and the aqueous layer was extracted with EtOAc (3×50 ml). Combined organic layers were dried over MgSO4 and concentrated. The residue was purified by chromatography
(EtOAc/Hexane=1:9) to give 1-benzyloxy-2(S)-hydroxy-4-pentent (2.6 g, 13.5 mmol)
NMR (CDCl3): 7.35 (bs, 5H), 5.84 (m, 1H), 5.14 (d, J=11, 1H), 5.11 (d, J=9, 1H), 4.57 (s, 2H), 3.90 (m, 1H), 3.53 (dd, J=3.4, 9.5, 1H), 3.39 (dd, J=7.4, 9.5, 1H) 2.29 (t, J=1.23, 2H).
EXAMPLE 17
Preparation of 2(R)-hydroxy-5(R)-iodomethyl tetra- hydrofuran
Solid NaHCO3 (3.6 g, 42.9 mmol) was added to a solution of 1-benzyloxy-2-(S)-hydroxy-4-pentene (1.1 g, 5.7 mmol) in dry CH3CN (25 ml) and the
resulting mixture was cooled to 0°C. To this mixture was added a solution of iodine (2.9 g) in dry
acetonitrile. Then the reaction mixture was stirred for 3 hours at 0°C. Saturated NaHCO3 (50 ml) was added to the reaction mixture. Solid NaHSO3 was added to the biphasic mixture until the iodine color disappeared. Organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 50 ml). Combined organic layers were dried over MgSO4 and was concentrated. The reside was purified by chromatography (EtOAc/hexane 1:1) to give the 20(S)-hydroxy-5(R)-iodomethyltetrahydrofuran (232.3 mg), a mixture of isomers (171.5 mg) and 2-(R)-hydroxy-5-(R)-iodomethyltetrahydrofuran (663.1 mg). NMR (CDCl3): 2-(S)-hydroxy-5-(R)-iodomethyltetrahydrofuran: 4.52 (m, 1H), 4.03 (m, 1H), 3.98 (dd, J=10.8, 1.5, 1H), 3.81 (dd, J=4.1, 10.8 1H), 3.44 (dd, J=10, 6.5, 1H), 3.36 (dd, J=10, 5.3, 1H), 2.36 (m, 1H), 1.84 (m, 1H).
2-(R)-hydroxy-5-(R)-iodomethyltetrahydrofuran:
4.58 (bs, 1H), 4.22 (m, 1H), 4.09 (dd, J=9.9,
4.1, 1H), 3.30 (d, J=5.6, 2H), 2.17 (dd, J=13.3,
5.8, 1H), 1.81 (m, 1H).
EXAMPLE 18
Preparation of 2(S,R)-(methylethyl)-3(S,R)-hydroxy- tetrahydrothiophene
Ethyl 3-mercaptopropionate (22.46 g) was dissolved in absolute ethanol (60 mL) and the solution was cooled to -20°C. To it was added sodium ethoxide solution in ethanol (62.5 mL of 21%). A solution of ethyl 2-bromoisovalerate (35 g) in absolute ethanol (60 mL) was added slowly. The reaction mixture was stirred for 2 hours while the reaction temperature was allowed to warm to room temperature. Saturated NH4Cl (150 mL) was added to the reaction mixture and organic layer was separated. The aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. Sodium (0.88 g) was dissolved in absolute ethanol (40 mL) at 0°C. and the solution was concentrated. The residue was
dissolved in toluene and the product from the previous reaction (7.78 g) was added. The reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temprature and 1N HCl was added to the reaction mixture until the pH became acidic. The crude product was extracted with EtOAc (50 mL × 3) and the combined organic layers were washei with brine, were dried over Na2SO4 and concentrated. The residue was heated with 10% H2SO4 (40 mL) at 100°C overnight. The crude product was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue (2(S,R)-(methylethyl)-tetrahydrothiophen-3-one) was dissolved in methylene chloride (60 mL) and the solution was cooled to 0°C.
Diisobutylaluminumhydride (25 mL, 1M) in methylene chloride was added dropwise. The reaction mixture was stirred for one hour at 0°C. The reaction was quenched by the dropwise addition of water until no gas
evolved. 1N HCl (50 mL) was added and the crude product was extracted with methylene chloride (50 mL × 3). Combined organic layers were washed with saturated NaHC03, brine and dried over Na2SO4. Concentration and purification by column chromatography, eluting with 20% ethyl acetate in hexane gave an oil (1.72 g):
1NMR (CDCl3): 4.36 (br, s, 1H), 3.1-2.85 (m, 3H), 2.23 (dd, J=6.8 Hz, 13.3 Hz, 1H), 1.95-1.77 (m, 3H), 1.07 (d, J=6.5 Hz, 3H), 1.02 (d, J=6.7 Hz, 3H). EXAMPLE 19
Preparation of 3(R,S)-[2(R,S)-methylethyl]tetra-hydrothienyl-2-pyridyl carbonate To a stirred solution of 2(R,S)-methylethyl- 3(R,S)-hydroxytetrahydrothiophene, 0.150 g and di (2 pyridyl) carbonate, 0.250 g in 3 mL of dry methylene chloride was added 0.185 mL of triethylamine. After stirring for 12 hours, the mixture was diluted with methylene chloride and washed with saturated aqueous NaHCO3 and brine and dried over anhydrous Na2SO4.
Filtration and concentration under reduced pressure gave the title compound as an oil.
EXAMPLE 20
Preparation of N-tert-butyl-decahydro-2[2(R)-hydroxy- 4-phenyl-3(S)-[1,1-dioxo-2(R)-methylethyl-3(R)- tetrahydrothienyloxycarbonylamino]butyl]-(4aS,8aS)- isoquinoline-3(S)-carboxamide. Compound C
To a stirred solution of 2(R,S)-methylethyl- 3(R,S)-tetrahydrothienyl 2-pyridyl carbonate, 0.203 g, and N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-aminobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide, 0.204 g in 5 mL of dry methylene chloride was added 0.093 mL of triethylamine. After stirring for 12 hours the mixture was diluted with methylene chloride and washed with saturated aqueous NaHCO3, brine and dried over anhydrous Na2SO4.
Filtration and concentration under reduced pressure gave a residue which was purified by
chromatography over silica gel. Elution with 1:4 ethyl acetate/hexane and by 1:1 ethyl acetate/hexane afforded 0.217 g of N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl'-3(R,S)-[2(R,S)-methylethyl-3(R,S)-tetrahydrothienyloxycarbonylamino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide. To a stirred solution of this compound and 0.250 g of N-methylmorpholine oxide in 10 mL of acetone and 2 mL of water was added 0.1 mL of a 2.5% solution of osmium tetroxide in 2-methyl-2-propanol. The mixture was stirred for 12 hours and 1.3 mL of saturated aqueous NaHSO3 was added to it. The mixture was extracted with methylene chloride (20 mL). The organic solution was washed with saturated aqueous NaHSO3, brine and dried over Na2SO4.
Filtration and concentration under reduced pressure gave a residue which was purified by
chromatography over silica gel. Elution with 1:1 ethyl acetate/hexane and by 3:1 ethyl acetate/hexane afforded 0.035 g of N-tert-butyl-decahydro-2[2(R)-hydroxy- 4-phenyl-3(S)-[1,1-dioxo-2(R)-methylethyl-3(R)-tetrahydrothienyloxycarbonylamino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white amorphous solid: m.p. 115 - 117°C;
1NMR (CDCl3): 7.29-7.18 (m, 5H), 5.80 (bs, 1H), 5.25 (bs, 1H), 3.99-3.82 (m, 3H), 3.20-2.85 (m, 5H), 2.66 (m, 2H), 2.31 (m, 2H), 1.36 (s, 9H), 1.17 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H).
Elemetnal analysis , calc'd for C33H51N3O6S × 0.60 CH2Cl2 × 0.05 H2O (657.70):
C, 59.54; H, 8.02; N, 6.39
Found: C, 59.53; H, 7.54; N, 6.23
Further elution with 5:95 methanol/chloroform gave N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-[1,1-dioxo-2(S)-methylethyl-3(S)-tetrahydrothienyloxycarbonylamino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide: m.p. 110-112°C.
Elemetnal analysis , calc'd for C33H51N3O6S × 0.75 H2O (654.49):
C, 62.06; H, 8.54; N, 6.78
Found: C, 62.02; H, 8.33; N, 6.40
EXAMPLE
Assay for Inhibition of Microbial Expressed Viral Protease
Inhibition studies of the reaction of the protease expressed in Escherichia coli with a peptide substrate [Val-Ser-Gln-Asn-(betanapthyl)Ala-Pro-Ile-Val, 0.5 mg/mL at the time the reaction is initiated] were in 50 mM Na acetate, pH 5.5, at 30°C for 1 hour. Various concentrations of inhibitor in 1.0 ul DMSO were added to 25 ul of the peptide solution in water. The reaction is initiated by the addition of 15 ul of 0.33 nM protease (0.11 ng) in a solution of 0.133 M Na acetate pH 5.5 and 0.26% bovine serum albumin. The reaction was quenched with 160 ul of 5% phosphoric acid. Products of the reaction were separated by HPLC (VYDAC wide pore 5 cm C-18 reverse phase, acetonitrile gradient, 0.1% phosphoric acid). The extent of
inhibition of the reaction was determined from the peak heights of the products. HPLC of the products,
independently synthesized, proved quantitation
standards and confirmation of the product composition. Compounds A , B and C showed IC50 values of about
260nM, 59nM and 4nM respectively.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention
encompasses all of the usual variations, adaptations, or modifications, as come within the scope of the following claims and its equivalents.
Claims
WHAT IS CLAIMED IS:
1.
R1 is a) 5- to 7- membered carbocylic ring which is either saturated, partially saturated or unsaturated, the carbocylic ring being unsubstituted or substituted with one or more of C1-4 alkyl, C2-4 alkenyl, C1-3 alkoxy, halo-C1-3 alkyl, aryl-C1-3 alkyl, or C3-5 cycloalkyl; or b) 5- to 7-membered heterocyle having one heteroatom selected from O or S, any of which heterocycle is unsubstituted or substituted with one or more of C1-4 alkyl, C2-4 alkenyl, oxo, C3-5
cycloalkyl, or C1-3 alkoxy; R2 is a) C1-5 alkyl, unsubstituted or substituted with one or more of -OH or C1-3 alkoxy; or
b) 5- to 7-membered carbocyclic ring which is either saturated, partially saturated or unsaturated, the carbocyclic ring being unsubstituted or substituted with one or more of C1-4 alkyl, C2-4 alkenyl, C1-3 alkoxy, or hydroxy;
R3 is a) Phenyl unsubstituted or substituted with one or more of -OH or C1-3 alkoxy; or b) C5-7 cycloalkyl unsubstituted or
substituted with one or more of -OH or C1-3 alkoxy, or pharmaceutically acceptable salt or hydrate thereof.
2 A compound according to Claim 1,
wherein:
R1 is a 5- to 7-membered heterocycle having one
heteroatom selected from 0 or S, any of which heterocycle is unsubstituted or substituted with one or more of C1-4 alkyl, C2-4 alkenyl, oxo or C1-3 alkoxy;
R2 is C1-5 alkyl, unsubstituted or substituted with one or more of -OH.
R3 is phenyl unsubstituted or substituted with -OH or C1-3 alkoxy.
A compound according to Claim 2
wherein:
R1 is 1,1-dioxo-tetrahydrothienyl or
tetrahydrofuranyl, unsubstituted or substituted with C1-4 alkyl, C2-4 alkenyl or C1-3 alkoxy;
R2 is t-butyl or 2-methylpropyl;
R3 is phenyl.
4. A compound according to Claim 3, wherein:
R1 is tetrahydrofuran-3-yl or
1,1-dioxo-tetrahydrothien-3-yl, unsubstituted or substituted with methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, or propenyl.
5. A compound according to Claim 1,
wherein:
R1 is a 5- to 7-membered heterocycle having one S heteratom, said heterocycle unsubstituted or substituted with one or more of C1-4 alkyl, oxo or C3-5 cycloalkyl
R2 is C1-5 alkyl;
R3 is phenyl;
A compound according to Claim 5, wherein:
R1 is 1,1-dioxotetrahydrothien-3-yl, unsubstituted or substituted with C1-4 alkyl, or C3-5 cycloalkyl
R2 is C1-5 alkyl;
R3 is phenyl.
The compound,
named:
c:s-N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-[3(S)-tetrahydrofuranyloxycarbonylamino]-butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide hydrate, or pharmaceutically acceptable salt thereof.
8. The compound,
Cis-N-tert-butyl-decahydro-2[2(R)-hydroxy-4-phenyl- 3(S)-[3(S)-1,1-dioxotetrahydrothien-3-yloxycarbonylamino]-butyl]-(4aS , 8aS)-isoquinoline-3(S)-carboxamide hydrate,
or pharmaceutically acceptable salt thereof.
9. The compound,
N-tert-butyl-decahydro-2[2-(R)-hydroxy-4-phenyl-3(S)- [1,1-dioxo-2(R)-methylethyl-3(R)-tetrahydrothienyloxycarbonylamino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide,
or pharmaceutically acceptable salt thereof.
10. Pharmaceutical composition, for use in the treatment of AIDS, in the prevention of infection by HIV, in the treatment of infection of HIV, or in the inhibition of HIV protease, comprising an effective amount of a compound as in any of Claims 1-9, and a pharmaceutically acceptable carrier.
11. A method of treating AIDS, comprising administering an effective amount of a compound as in any Claims 1-9.
12. A method of preventing infection by HIV, comprising administering an effective amount of a compound as in any of Claims 1-9.
13. A method of treating infection by HIV, comprising administering an effective amount of a compound as in any of Claims 1-9.
14. A method of inhibiting HIV protease, comprising administering an effective amount of a compound as in any of Claims 1-9.
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US78147091A | 1991-10-23 | 1991-10-23 | |
US781,470 | 1991-10-23 | ||
US92999192A | 1992-08-21 | 1992-08-21 | |
US929,991 | 1992-08-21 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE42889E1 (en) | 1992-08-25 | 2011-11-01 | G.D. Searle Llc | α- and β- amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
USRE43596E1 (en) | 1992-08-25 | 2012-08-21 | G.D. Searle Llc | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
Families Citing this family (51)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6313094B1 (en) | 1990-12-11 | 2001-11-06 | Japan Energy Corporation | β-amino-α-hydroxycarboxylic acid derivatives and HIV protease inhibitors |
US5413999A (en) * | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
US6071895A (en) | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
NZ249789A (en) | 1992-03-11 | 1997-07-27 | Narhex Ltd | Hydrazine, carbazate and 1,2-diazacyclic derivatives and pharmaceutical compositions |
DE69333270T2 (en) | 1992-03-11 | 2004-08-05 | Narhex Ltd. | AMINE DERIVATIVES OF OXO AND HYDROXY SUBSTITUTED CARBON HYDROGEN |
US5888992A (en) | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
US5484926A (en) | 1993-10-07 | 1996-01-16 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
US5846993A (en) * | 1992-12-22 | 1998-12-08 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
AU6828894A (en) * | 1993-05-14 | 1994-12-12 | Merck & Co., Inc. | Hiv protease inhibitors |
PL314984A1 (en) * | 1993-12-15 | 1996-09-30 | Merck & Co Inc | Hiv protease inhibitors |
US5733882A (en) * | 1994-01-17 | 1998-03-31 | Smithkline Beecham Corporation | Retroviral protease inhibitors |
US5480887A (en) * | 1994-02-02 | 1996-01-02 | Eli Lilly And Company | Protease inhibitors |
AU8074894A (en) * | 1994-02-02 | 1995-08-21 | Eli Lilly And Company | Hiv protease inhibitors and intermediates |
US5527829A (en) * | 1994-05-23 | 1996-06-18 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
US6222043B1 (en) | 1995-06-30 | 2001-04-24 | Japan Energy Corporation | Methods of preparing novel dipeptide compounds or pharmaceutically acceptable salts thereof |
US5932550A (en) * | 1995-06-30 | 1999-08-03 | Japan Energy Corporation | Dipeptide compound or pharmaceutically acceptable salt thereof and medical use thereof |
DE19531685A1 (en) * | 1995-08-29 | 1997-03-06 | Bayer Ag | New heterocyclically substituted pseudopeptides |
US5925759A (en) | 1996-09-05 | 1999-07-20 | Agouron Pharmaceuticals, Inc. | Methods of making HIV-protease inhibitors and intermediates for making HIV-protease inhibitors |
US5962725A (en) | 1996-09-05 | 1999-10-05 | Agouron Pharmaceuticals, Inc. | Intermediate compounds useful for making HIV protease inhibitors such as nelfinavir |
US5705647A (en) * | 1996-09-05 | 1998-01-06 | Agouron Pharmaceuticals, Inc. | Intermediates for making HIV-protease inhibitors |
WO1998029118A1 (en) | 1996-12-27 | 1998-07-09 | Japan Energy Corporation | Novel tripeptide compounds and anti-aids drugs |
US6001851A (en) * | 1997-03-13 | 1999-12-14 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
US6084107A (en) * | 1997-09-05 | 2000-07-04 | Agouron Pharmaceuticals, Inc. | Intermediates for making HIV-protease inhibitors |
EP1039886A4 (en) * | 1997-12-08 | 2001-05-16 | Scripps Research Inst | A SMALL P3 REMAINING HIV / FIV PROTEASE INHIBITOR |
US6803466B1 (en) * | 1997-12-08 | 2004-10-12 | The Scripps Research Institute | HIV/FIV protease inhibitors having a small P3 residue |
WO1999067254A2 (en) * | 1998-06-23 | 1999-12-29 | The United States Of America Represented By The Secretary, Department Of Health And Human Services | Multi-drug resistant retroviral protease inhibitors and use thereof |
PT2336134T (en) | 1998-06-23 | 2016-10-19 | The Board Of Trustees Of The Univ Of Illionis | Fitness assay and methods for reducing resistance of hiv to therapy |
US6613764B1 (en) | 1999-01-06 | 2003-09-02 | The United States Of America As Represented By The Department Of Health And Human Services | Aspartic protease inhibitors |
AU5771500A (en) * | 1999-06-28 | 2001-01-31 | Oklahoma Medical Research Foundation | Catalytically active recombinant memapsin and methods of use thereof |
JP2003531865A (en) * | 2000-04-28 | 2003-10-28 | アメリカ合衆国 | Improving immunogenicity using a combination of DNA and vaccinia virus vector vaccines |
CA2473231A1 (en) * | 2002-01-07 | 2003-08-07 | Sequoia Pharmaceuticals | Resistance-repellent retroviral protease inhibitors |
US7157489B2 (en) * | 2002-03-12 | 2007-01-02 | The Board Of Trustees Of The University Of Illinois | HIV protease inhibitors |
AU2003301841A1 (en) * | 2002-05-01 | 2004-06-07 | National Institutes Of Health | Immunotherapy regimens in hiv-infected patients |
EP1589018A4 (en) | 2002-12-27 | 2007-03-14 | Sumitomo Chemical Co | PROCESS FOR PRODUCING A DERIVATIVE OF HEXAHYDROFURANOL, INTERMEDIATE THEREOF AND PROCESS FOR PRODUCING THE SAME |
CA2559328A1 (en) * | 2004-03-11 | 2005-09-22 | Sequoia Pharmaceuticals, Inc. | Resistance-repellent retroviral protease inhibitors |
JP2005314374A (en) * | 2004-03-31 | 2005-11-10 | Daiso Co Ltd | New method for producing 3-hydroxythiolane |
US7378441B2 (en) | 2004-05-07 | 2008-05-27 | Sequoia Pharmaceuticals, Inc. | Resistance-repellent retroviral protease inhibitors |
CA2618508A1 (en) * | 2005-08-10 | 2007-02-22 | Oklahoma Medical Research Foundation | Truncated memapsin 2 for use for treating alzheimer's disease |
US20090087456A1 (en) * | 2005-09-07 | 2009-04-02 | James Edward Eyles | Adjuvanted vaccine |
GB0519871D0 (en) * | 2005-09-30 | 2005-11-09 | Secr Defence | Immunogenic agents |
US8323664B2 (en) * | 2006-07-25 | 2012-12-04 | The Secretary Of State For Defence | Live vaccine strains of Francisella |
GB0900455D0 (en) | 2009-01-13 | 2009-02-11 | Secr Defence | Vaccine |
GB0901411D0 (en) | 2009-01-29 | 2009-03-11 | Secr Defence | Treatment |
GB0901423D0 (en) | 2009-01-29 | 2009-03-11 | Secr Defence | Treatment |
GB0906234D0 (en) | 2009-04-14 | 2009-05-20 | Secr Defence | Vaccine |
WO2011106705A2 (en) | 2010-02-26 | 2011-09-01 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Dna-protein vaccination protocols |
KR101680302B1 (en) * | 2010-07-13 | 2016-11-29 | 김찬숙 | Composition for inducing multiple nuclear division of cells |
LT2643326T (en) | 2010-11-23 | 2017-02-27 | Mylan Laboratories, Limited | Process for the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol |
ES2657227T3 (en) | 2012-08-09 | 2018-03-02 | Sumitomo Chemical Company, Limited | Method to produce a hexahydrofurofuranol derivative |
US20180346520A1 (en) | 2015-05-13 | 2018-12-06 | The United States Of America As Represented By The Secretary Of The Department Of Health And | Methods and compositions for inducing an immune response using conserved element constructs |
EP4551247A1 (en) | 2022-07-07 | 2025-05-14 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Immunogens and methods for inducing an immune response |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0346847A2 (en) * | 1988-06-13 | 1989-12-20 | F. Hoffmann-La Roche Ag | Amino acid derivatives |
EP0432695A2 (en) * | 1989-12-11 | 1991-06-19 | F. Hoffmann-La Roche Ag | Amino acid derivatives |
EP0434365A2 (en) * | 1989-12-18 | 1991-06-26 | Merck & Co. Inc. | HIV protease inhibitors useful for the treatment of aids |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2012306A1 (en) * | 1989-03-28 | 1990-09-28 | Werner Neidhart | Amino acid derivatives |
GB8927915D0 (en) * | 1989-12-11 | 1990-02-14 | Hoffmann La Roche | Novel alcohols |
-
1992
- 1992-10-14 WO PCT/US1992/008758 patent/WO1993008184A1/en active Search and Examination
- 1992-10-16 NZ NZ244773A patent/NZ244773A/en unknown
- 1992-10-16 IL IL103459A patent/IL103459A0/en unknown
- 1992-10-21 ES ES92309639T patent/ES2125251T3/en not_active Expired - Lifetime
- 1992-10-21 EP EP92309639A patent/EP0539192B1/en not_active Expired - Lifetime
- 1992-10-21 DE DE69228106T patent/DE69228106T2/en not_active Expired - Fee Related
- 1992-10-21 AT AT92309639T patent/ATE175412T1/en not_active IP Right Cessation
- 1992-10-22 CA CA002081134A patent/CA2081134A1/en not_active Abandoned
- 1992-10-22 AU AU27253/92A patent/AU649170B2/en not_active Ceased
- 1992-10-23 JP JP4309474A patent/JPH0678314B2/en not_active Expired - Lifetime
-
1994
- 1994-10-25 US US08/328,936 patent/US5502060A/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0346847A2 (en) * | 1988-06-13 | 1989-12-20 | F. Hoffmann-La Roche Ag | Amino acid derivatives |
EP0432695A2 (en) * | 1989-12-11 | 1991-06-19 | F. Hoffmann-La Roche Ag | Amino acid derivatives |
EP0434365A2 (en) * | 1989-12-18 | 1991-06-26 | Merck & Co. Inc. | HIV protease inhibitors useful for the treatment of aids |
Non-Patent Citations (1)
Title |
---|
SCIENCE vol. 248, 20 April 1990, LANCASTER, PA US pages 358 - 361 NOEL A. ROBERTS ET AL 'Rational design of peptide-based HIV proteinase inhibitors' * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE42889E1 (en) | 1992-08-25 | 2011-11-01 | G.D. Searle Llc | α- and β- amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
USRE43596E1 (en) | 1992-08-25 | 2012-08-21 | G.D. Searle Llc | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
USRE43802E1 (en) | 1992-08-25 | 2012-11-13 | G.D. Searle Llc | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
Also Published As
Publication number | Publication date |
---|---|
JPH0678314B2 (en) | 1994-10-05 |
EP0539192B1 (en) | 1999-01-07 |
DE69228106T2 (en) | 1999-07-15 |
EP0539192A1 (en) | 1993-04-28 |
US5502060A (en) | 1996-03-26 |
AU649170B2 (en) | 1994-05-12 |
IL103459A0 (en) | 1993-03-15 |
DE69228106D1 (en) | 1999-02-18 |
NZ244773A (en) | 1994-10-26 |
ES2125251T3 (en) | 1999-03-01 |
ATE175412T1 (en) | 1999-01-15 |
CA2081134A1 (en) | 1993-04-24 |
AU2725392A (en) | 1993-04-29 |
JPH05239031A (en) | 1993-09-17 |
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